Phenol derivatives and pharmaceutical or cosmetic use thereof

ABSTRACT

The present invention relates to novel compounds of general formula: 
                         
and to the cosmetic or pharmaceutical use thereof.

CROSS-REFERENCE TO PRIOR APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/519,100, filed Jul. 16, 2013, now issued as U.S. Pat. No. 9,050,266,which is a National Stage of PCT/FR2010/052871, filed Dec. 22, 2010, anddesignating the United States (published in French on Jun. 30, 2011, asWO 2011/077043 A2; the title and abstract were published in English),which claims priority of FR 0959475, filed Dec. 23, 2009, and U.S.Provisional Patent Application No. 61/282,153, filed Dec. 23, 2009, eachhereby expressly incorporated by reference in its entirety and eachassigned to the assignee hereof.

The present invention relates to novel compounds of general formula:

and to the cosmetic or pharmaceutical use thereof.

The present invention proposes to provide novel phenolic derivativeswhich are powerful androgen receptor modulators.

Among the prior art documents describing molecules which modulateandrogen receptor activity, mention may, for example, be made of thephenylimidazolines described in patent application EP 580 459, orapplication WO 2005/42464.

The invention relates to novel phenolic derivatives that correspond togeneral formula (I) below:

in which:

-   -   R₁ represents a C₂₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy,        —S(O)_(m)—C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy,        —(CH₂)_(n)—C₃₋₉ cycloalkyl, —(CH₂)_(n)—C₃₋₉ cycloalkyl, C₂₋₆        alkyl-OH, —(CH₂)_(n)—C₁₋₆ alkyloxy, —(CH₂)_(n)—C₁₋₆ fluoroalkyl,        —(CH₂)_(p)—O—C₁₋₆ fluoroalkyl, COR_(a), CN, NO₂ or NR₈R₉ group,        a halogen or a phenyl or heteroaryl group containing either a)        from 1 to 4 nitrogen atoms or b) an oxygen or sulphur atom and 1        or 2 nitrogen atom(s). These phenyl and heteroaryl groups may be        optionally substituted with one to three identical or different        R_(b) groups.    -   R₂ and R₃ are identical or different and represent a hydrogen        atom or a C₁₋₉ alkyl, C₃₋₉ cycloalkyl, C₁₋₆ fluoroalkyl,        —(CH₂)_(r)—C₃₋₉ cycloalkyl, —C₂₋₆ alkyl-OH, —(CH₂)_(r)—C₁₋₆        alkyloxy, —(CH₂)_(r)—C₃₋₇ cycloalkyl, —(CH₂)_(r)—C₁₋₆        fluoroalkyl, or —(CH₂)_(q)—O—C₁₋₆ fluoroalkyl group.    -   Optionally, the R₂ and R₃ groups can form, with the carbon atom        which bears them, a C₃₋₉ cycloalkyl group or a heterocycle such        as tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran,        tetrahydro-1-oxythiopyran or tetrahydro-1,1-dioxythiopyran.    -   R₄, R₅, R₆, R₇ are identical or different and represent either a        hydrogen atom or a C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy,        —S(O)_(s)—C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy,        —(CH₂)_(t)—C₃₋₉ cycloalkyl, —(CH₂)_(t)—C₃₋₉ cycloalkyl, —C₁₋₆        alkyl-OH, —(CH₂)_(t)C₁₋₆ alkyloxy, —(CH₂)_(t)—C₁₋₆ fluoroalkyl,        —(CH₂)_(u)—O—₁₋₆ fluoroalkyl, COR_(d), CN or NR_(8′)R_(9′)        group, or a halogen or a phenyl or heteroaryl group containing        either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulphur        atom and 1 or 2 nitrogen atom(s). These phenyl and heteroaryl        groups may be optionally substituted with one to three identical        or different R_(c) groups.    -   X represents CH or N.    -   Y represents either a nitrogen atom, or a carbon atom        substituted with a C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy,        —S(O)_(v)C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy,        —(CH₂)_(l)—C₃₋₉ cycloalkyl, —(CH₂)_(l)—C₃₋₉ cycloalkyl, C₁₋₆        alkyl-OH, —(CH₂)_(l)—C₁₋₆ alkyloxy, —(CH₂)_(l)—C₁₋₆ fluoroalkyl,        —(CH₂)_(w)—O—C₁₋₆ fluoroalkyl, COR_(e), CN, NR₁₀R₁₁ or NO₂        group, a hydrogen atom or a halogen or a phenyl or heteroaryl        group containing either a) from 1 to 4 nitrogen atoms or b) an        oxygen or sulphur atom and 1 or 2 nitrogen atom(s). These phenyl        or heteroaryl groups may be optionally substituted with one to        three identical or different Rb groups;    -   Ra, Rd and Re are identical or different and represent a C1-6        alkyl, C1-6 alkyloxy or NR12R13 group.    -   Rb and Rc are identical or different and represent a halogen, or        a C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy, —S(O)_(j)—C₁₋₆        alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy, —(CH₂)_(i)—C₃₋₇        cycloalkyl, OH, —(CH₂)_(i)—C₃₋₇ cycloalkyl, C₁₋₆ alkyl-OH,        —(CH₂)_(i)—C₁₋₆ alkyloxy, —(CH₂)_(i)—C₁₋₆ fluoroalkyl,        —(CH₂)_(z)—O—C₁₋₆ fluoroalkyl, COR_(a), CN or NR₁₄R₁₅ group.    -   R₈ and R_(8′) are identical or different and represent a C₁₋₆        alkyl, C₃₋₇ cycloalkyl, —(CH₂)_(f)—C₃₋₇ cycloalkyl or        —(CH₂)_(f)—C₁₋₆ fluoroalkyl group.    -   R₉, R_(9′), R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₅ are identical or        different and represent a a hydrogen atom or a C₁₋₆ alkyl, C₃₋₇        cycloalkyl, —(CH₂)_(g)—C₃₋₇ cycloalkyl or —(CH₂)_(g)—C₁₋₆        fluoroalkyl group.    -   Optionally, the R₈ and R₉ groups can form, with the nitrogen        atom which bears them, a heterocycle such as: azetidine,        pyrrolidine, piperidine, azepane, morpholine or piperazine.        Optionally, the R_(8′) and R_(9′) groups can form, with the        nitrogen atom which bears them, a heterocycle such as:        azetidine, pyrrolidine, piperidine, azepane, morpholine or        piperazine. Optionally, the R₁₀ and R₁₁ groups can form, with        the nitrogen atom which bears them, a heterocycle such as:        azetidine, pyrrolidine, piperidine, azepane, morpholine or        piperazine. Optionally, the R₁₂ and R₁₃ groups can form, with        the nitrogen atom which bears them, a heterocycle such as:        azetidine, pyrrolidine, piperidine, azepane, morpholine or        piperazine. Optionally, the R₁₄ and R₁₅ groups can form, with        the nitrogen atom which bears them, a heterocycle such as:        azetidine, pyrrolidine, piperidine, azepane, morpholine or        piperazine.    -   f, g, i, l, n, r and t are different or identical and are equal        to 1, 2 or 3    -   j, m, s and v are different or identical and are equal to 0, 1        or 2    -   p, q, u, w and z are different or identical and are equal to 2,        3 or 4        and also the pharmaceutically acceptable salts, solvates or        hydrates thereof and the conformers or rotamers thereof.

The compounds of formula (I) may comprise one or more asymmetric carbonatoms. They may thus exist in the form of a mixture of enantiomers or ofdiastereoisomers. These enantiomers and diastereoisomers, and alsomixtures thereof, including racemic mixtures, form part of theinvention.

The compounds of formula (I) may exist in the form of bases or ofacid-addition salts. Such addition salts form part of the invention.These salts are advantageously prepared with pharmaceutically acceptableacids, but the salts of other acids that are useful, for example forpurifying or isolating the compounds of formula (I), also form part ofthe invention. These acids may be, for example, picric acid, oxalic acidor an optically active acid, for example a tartaric acid, adibenzoyltartaric acid, a mandelic acid or a camphorsulphonic acid, andthose that form physiologically acceptable salts, such as hydrochloride,hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate,maleate, fumarate, 2-naphthalenesulphonate or para-toluenesulphonate.For a review of physiologically acceptable salts, see the Handbook ofPharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth(Wiley-VCH, 2002).

The solvates or hydrates may be obtained directly after the synthesisprocess, compound (I) being isolated in the form of a hydrate, forexample a monohydrate or hemihydrate, or of a solvate of the reaction orpurification solvent.

In the context of the invention, the following definitions apply:

-   -   C_(b-c) in which b and c may take values from 1 to 9: a        carbon-based chain of b to c carbon atoms, for example C₁₋₆ is a        carbon-based chain that may contain from 1 to 6 carbon atoms,    -   alkyl: a linear or branched saturated aliphatic group, for        example a C₁₋₆ alkyl group represents a linear or branched        carbon-based chain of 1 to 6 carbon atoms, preferably a methyl,        ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or        hexyl group,    -   cyloalkyl: a cyclic, optionally branched, saturated carbon-based        chain containing from 3 to 7 carbon atoms. By way of example, a        C₃₋₇ cycloalkyl group represents a carbon-based chain containing        from 3 to 7 carbon atoms, preferably a cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl or cycloheptyl,    -   heterocycle: a cyclic or bicyclic, saturated or unsaturated        hydrocarbon-based chain comprising one or more heteroatoms        chosen from O, S and N,    -   heteroaryl: an aromatic heterocycle, preferably a pyridinyl,        pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyrazolyl,        isooxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl or        imidazolyl group,    -   halogen: a fluorine, chlorine or bromine atom,    -   alkyloxy: an —O-alkyl group,    -   alkylthio: an —S-alkyl group,    -   fluoroalkyl: an alkyl group in which one or more hydrogen atoms        have been replaced with a fluorine atom,    -   fluoroalkyloxy: an alkyloxy group in which one or more hydrogen        atoms have been replaced with a fluorine atom.

The group (A) of the compounds of formula (I) defined above ispreferred, in which compounds:

-   -   X represents CH and Y represents a carbon atom substituted by        one of the groups as defined above and preferably a methyl,        ethyl, isopropyl, cyclopropyl, CF₃, CONH₂, CO₂CH₃, CO₂CH₂CH₃,        CN, NO₂, SCH₃ or SCH₂CH₃ group, a hydrogen atom, a halogen or a        OCF₃, OCH₃, OCH₂CH₃ or OCH(CH₃)₂ group.

The group (B) of the compounds of formula (I), the substituents X and Yof which are defined above or in the preferred group (A) and such thatthe group R₁ represents a halogen, an ethyl, isopropyl, trifluoromethyl,nitrile, nitro, methoxy, ethoxy, isopropoxy, thiomethyl, thioethyl orthioisopropyl group, is a group of preferred compounds and moreparticularly such that R₁ represents a halogen or a methoxy, ethoxy,thiomethyl, thioethyl or trifluoromethyl group.

The compounds below, and the pharmaceutically acceptable salts, solvatesand hydrates, and the conformers or rotamers thereof, are particularlypreferred:

-   2-[(6-Methoxypyridin-2-ylamino)methyl]phenol-   2-[(6-Bromopyridin-2-ylamino)methyl]phenol-   2-[(6-Bromopyridin-2-ylamino)methyl]-4-fluorophenol-   6-(2-Hydroxybenzylamino)pyridine-2-carbonitrile-   2-[1-(6-Methoxypyridin-2-ylamino)ethyl]phenol-   2-[(6-Trifluoromethylpyridin-2-ylamino)methyl]phenol-   2-[(6-Chloropyridin-2-ylamino)methyl]phenol-   2-[(6-Ethylpyridin-2-ylamino)methyl]phenol-   2-[(6-Ethoxypyridin-2-ylamino)methyl]phenol-   2-[(6-Isopropoxypyridin-2-ylamino)methyl]phenol-   5-Chloro-2-[(6-methoxypyridin-2-ylamino)methyl]phenol-   2-[(2-Trifluoromethylpyrimidin-4-ylamino)methyl]phenol-   2-[(6-Bromopyrazin-2-ylamino)methyl]phenol-   2-[(2-Chloropyrimidin-4-ylamino)methyl]phenol-   2-[(2-Bromopyrimidin-4-ylamino)methyl]phenol-   2-[(2-Chloro-6-methylpyrimidin-4-ylamino)methyl]phenol-   2-[(6-Chloro-4-trifluoromethylpyridin-2-ylamino)methyl]phenol-   2-[(6-Chloro-4-methylpyridin-2-ylamino)methyl]phenol-   2-[(6-Methoxypyrazin-2-ylamino)methyl]phenol-   2-[(2-Methoxypyrimidin-4-ylamino)methyl]phenol-   2-[(2-Methoxy-6-methylpyrimidin-4-ylamino)methyl]phenol-   2-[(6-Methylsulphanylpyridin-2-ylamino)methyl]phenol-   2-[(6-Methanesulphinylpyridin-2-ylamino)methyl]phenol-   2-[(6-Methanesulphonylpyridin-2-ylamino)methyl]phenol-   2-[(6-Methoxypyridin-2-ylamino)methyl]-6-methylphenol-   2-[(4-Bromo-6-methoxypyridin-2-ylamino)methyl]phenol-   2-[(6-Bromo-2-methoxypyrimidin-4-ylamino)methyl]phenol-   2-[(4-Chloro-6-methoxypyridin-2-ylamino)methyl]phenol-   2-[(6-Bromo-2-methoxypyrimidin-4-ylamino)methyl]phenol-   2-[(4-Bromo-6-methoxypyridin-2-ylamino)methyl]-6-fluorophenol-   2-[(4-Bromo-6-methoxypyridin-2-ylamino)methyl]-5-fluorophenol-   2-[(4-Bromo-6-methoxypyridin-2-ylamino)methyl]-3-fluorophenol-   2-[(4-Bromo-6-methoxypyridin-2-ylamino)methyl]-4-fluorophenol-   2-[(6-Bromo-2-methoxypyrimidin-4-ylamino)methyl]-4-fluorophenol-   2-[(4-Chloro-6-methoxypyridin-2-ylamino)methyl]-4-fluorophenol-   2-[(6-Chloro-2-methoxypyrimidin-4-ylamino)methyl]-4-fluorophenol-   2-[1-(4-Bromo-6-methoxypyridin-2-ylamino)ethyl]phenol-   2-[1-(4-Bromo-6-methoxypyridin-2-ylamino)propyl]phenol-   2-[1-(6-Bromo-4-methylpyridin-2-ylamino)-1-methylethyl]phenol-   2-[1-(4-Bromo-6-methoxypyridin-2-ylamino)propyl]-4-fluorophenol-   2-[1-(6-Bromopyridin-2-ylamino)propyl]-4-fluorophenol-   4-Fluoro-2-[(6-methoxypyridin-2-ylamino)methyl]phenol-   4-Fluoro-2-[(6-methoxypyridin-2-ylamino)ethyl]phenol-   4-Fluoro-2-[(6-methoxypyridin-2-ylamino)propyl]phenol-   2-[(6-Bromo-4-methoxypyridin-2-ylamino)methyl]phenol-   2-[(6-Bromo-4-methylpyridin-2-ylamino)methyl]phenol-   2-[(6-Chloro-4-methoxypyridin-2-ylamino)methyl]phenol

A subject of the invention is also a process for preparing the compoundsof general formula (I).

In accordance with the invention, the compounds of formula (I) can beprepared by one of the three methods described in Scheme 1 below andoptionally completed by one or more of the reactions as described inScheme 2.

The phenolic compounds of formula (I) in which R₁, R₂, R₃, R₄, R₅, R₆,R₇, X and Y are as defined above can be prepared by means of a reductiveamination reaction between an aldehyde or a benzyl ketone (II) and anamine (III) in the presence of a reducing agent, such as, for example,and in a non-limiting manner, sodium triacetoxyborohydride, according toMethod 1a illustrated in Scheme 1 and by analogy, for example, with thereactions described in Org. Pro. R. & D. (2006) 971-1031.

The phenolic compounds of formula (I) can be prepared by reactionbetween heterocycles (V) comprising a leaving group and benzyl amines inthe presence of a base such as, in a non-limiting manner,1,8-diazabicyclo[5.4.0]undec-7-ene, for example in a solvent such asdimethyl sulphoxide and as described by Method 1b of Scheme 1. The term“leaving group” denotes a group well known to those skilled in the art,such as, in a non-limiting manner, a halogen, a mesylate, a tosylate ora triflate.

The third method of preparing phenolic compounds of formula (I) consistsin reducing amide intermediates (VII) using a reactive hydrogen donorsuch as, in a non-limiting manner, lithium aluminium hydride asillustrated by Method 1c of Scheme 1. These amide intermediates may beprepared by reaction between, for example, and in a non-limiting manner,an acyl chloride (VI) and an amine (III) in pyridine. The acyl chlorides(VI) are prepared from the acids according to techniques well known tothose skilled in the art, for example at reflux in thionyl chloride.

Certain compounds comprising a sulphoxy group (X) or sulphone group (XI)may optionally be prepared by oxidation of the thioether intermediate(IX) as described in Scheme 2 according to Method 2a. The oxidation mayfor example, and in a non-limiting manner, be carried out by oxone. Thethioether intermediate (IX) may be prepared from compounds (VIII)comprising a leaving group such as, in a non-limiting manner, a chlorineatom, by reaction with a thiolate in dimethyl sulphoxide. Certaincompounds comprising an ether group may optionally be prepared byreaction of the intermediate (VIII) with the corresponding alcohol suchas, for example, and in a non-limiting manner, methanol in the presenceof a base such as sodium hydroxide, optionally by heating in a microwaveoven and as described in Scheme 2 according to Method 2b.

The functional groups optionally present in the reaction intermediatesused in the process may be protected, either permanently or temporarily,with protecting groups that ensure an unequivocal synthesis of theexpected compounds. The protection and deprotection reactions areperformed according to techniques that are well known to those skilledin the art. The term “temporary protecting group for amines, alcohols orcarboxylic acids” means protecting groups such as those described in“Protective Groups in Organic Chemistry”, edited by McOmie J. W. F.,Plenum Press, 1973, in “Protective Groups in Organic Synthesis”, 2ndedition, Greene T. W. and Wuts P. G. M., published by John Wiley & Sons,1991, and in “Protecting Groups”, Kocienski P. J., 1994, Georg ThiemeVerlag.

The products which are subjects of the present invention haveadvantageous pharmacological properties; it was in particular noted thatthey modulate androgen receptor activity.

Tests given in the experimental section illustrate this androgenreceptor-modulating activity. The products which are subjects of thepresent invention exhibit partial or total antagonist or agonistactivities. Because of this activity, the products of the invention canbe used as medicaments in humans or animals.

These properties make the products of general formula (I) of the presentinvention usable as medicaments for treating hormone-dependent cancerssuch as prostate cancer or breast cancer, and also for combating benignprostatic hyperplasia, early puberty, virilization, polycystic ovarysyndrome, Stein-Leventhal syndrome, loss of libido, or endometriosis.The compounds exhibiting partial or total agonist activity can inparticular be used for treating afflictions such as loss of muscle mass(sarcopenia), muscle atrophy, impotence and male sterility, abnormalmale differentiation (hermaphroditism), hypogonadism or osteoporosis.The products of general formula (I) of the invention find a cosmetic usein a compound for body or hair hygiene.

The products of general formula (I) of the invention also find a use inthe treatment of hirsutism, acne, seborrhoea, oily skin, androgenicalopecia or hyperpilosity, and they can be used for the production of amedicament for preventing and/or treating hirsutism, androgenicalopecia, hyperpilosity, atopic dermatitis, or sebaceous gland disorderssuch as hyperseborrhoea, acne, oily skin or seborrhoeic dermatitis. Theproducts of formula (I) can therefore be used in dermatology: they canbe used alone or in combination. They can be combined in particular withan antibiotic product, such as derivatives of azelaic acid, fusidic acidor erythromycin, or with a retinoid derivative such as tretinoin for thetreatment of acne, or with a 5a-reductase inhibitor such as (5alpha,17beta)-N-1,1-dimethylethyl-3-oxo-4-azaandrost-1-ene-17-carboxamide (orFinasteride, Merck, 13th Edition) or azelaic acid or an androgenreceptor-blocking agent for the treatment of acne, alopecia orhirsutism, or with a product that stimulates hair growth, such asMinoxidil, for the treatment of alopecia.

A subject of the present invention is also, as medicament, the compoundsof formula (I) as described above, and also the pharmaceuticallyacceptable salts and pharmaceutically acceptable solvates and/orhydrates thereof.

Several examples of preparation of active compounds of formula (I)according to the invention, and the results of the biological activityof such compounds, are given hereinbelow as illustrations and with nolimiting nature.

PROCEDURES Example 1 2-[(6-Methoxypyridin-2-ylamino)methyl]phenol

Synthesis According to Scheme 1, Method 1a

512 mg (2.41 mmol, 1.5 eq) of sodium triacetoxyborohydride are added toa solution of 200 mg (1.61 mmol, 1 eq) of 6-methoxypyridin-2-ylamine(starting material 1) and 236 mg (2.41 mmol, 1 eq) of2-hydroxybenzaldehyde (starting material 2) in 20 ml of tetrahydrofuran.The solution is stirred at room temperature for 48 h. It is evaporatedand the residue is taken up in 100 ml of dichloromethane and thenextracted with a saturated aqueous solution of ammonium chloride. Theaqueous phase is extracted twice with dichloromethane. The organicphases are combined and dried over sodium sulphate. The residue ischromatographed on silica gel (5/95 ethyl acetate/heptane).2-[(6-methoxypyridin-2-ylamino)methyl]phenol is obtained in the form ofa white solid. Melting point=103° C.

¹H NMR (CDCl₃): 3.94 (s, 3H); 4.52 (d, 2H, J=3.08 Hz); 4.95 (s, 1H),6.03 (dd, 2H, J=6.2 Hz, J′=1.64 Hz); 6.85 (t, 1H, J=6.28 Hz, J′=7.4 Hz);6.95 (d, 1H, J=9.04 Hz); 7.15-7.23 (m, 2H); 7.36 (t, 1H, J=7.92 Hz,J′=7.96 Hz); 10.21 (s, 1H)

Preparation of the 6-aminopyridine-2-carbonitrile intermediate

340 mg (2.89 mmol, 1 eq) of zinc cyanide are added to 500 mg (2.89 mmol,1 eq) of 6-bromopyridin-2-ylamine in 10 ml of dimethylformamide in amicrowave tube. 170 mg (0.147 mmol, 0.05 eq) oftetrakis(triphenylphosphine)palladium are added. The medium is heated at170° C. for 1 hour 30 minutes in a microwave oven. 50 ml of ethylacetate are added to the medium, which is filtered over celite. Thefiltrate is washed with water and extracted with ethyl acetate. Theorganic phases are combined and dried over sodium sulphate. The residueis triturated in heptane. 6-Aminopyridine-2-carbonitrile is obtained inthe form of an orange solid.

Melting point=92° C.

Preparation of the 6-ethoxypyridin-2-ylamine intermediate

Introduced into a microwave tube are 500 mg (2.89 mmol) of2-amino-6-bromopyridine, to which 2 ml of ethanol and 231 mg (5.78 mmol,2 eq) of sodium hydroxide are added. The mixture is heated for 10 hoursin a microwave oven at 170° C. The reaction medium is diluted with 50 mlof dichloromethane and then washed twice with 50 ml of water. Theorganic phase is concentrated to dryness and the residue is purified bychromatography over silica with, as eluent, heptane/ethyl acetate (1/1).The expected product is obtained in the form of a colourless oil.

Preparation of the 6-isopropoxypyridin-2-ylamine intermediate

This intermediate is prepared according to the procedure described for6-ethoxypyridin-2-ylamine, replacing the ethanol with isopropanol. Theexpected product is obtained in the form of a colourless oil.

Examples 2 to 12

Examples 2 and 12 are described in Table 1 below. The compounds aresynthesized according to the procedure described above, replacing thestarting materials 1 and 2 mentioned in Example 1 with the productsmentioned in Table 1.

TABLE 1 ¹H NMR - 400 MHz (s = singlet, d = doublet, t = triplet, m =multiplet, q = IUPAC Starting Starting Melting quartet, J = couplingExample # name material 1 material 2 point (° C.) constant in Hz) 22-[(6- 2-bromo- 2- 127 (CDCl₃) 4.48 (d, 2H, J = 4.28 Hz); bromo-pyridin-6- hydroxy- 5.17 (s, 1H); 6.35 (d, 1H, pyridin-2- ylaminebenzaldehyde J = 8.7 Hz); 6.77 (d, 1H, J = 7.3 Hz); ylamino)- 6.87 (t,1H, J = 7.4 Hz); methyl]- 7.0 (d, 1H, J = 9.1 Hz); phenol 7.16-7.27 (m,3H); 9.84 (s, 1H) 3 2-[(6- 6-bromo- 5-fluoro- 143 (DMSO) 4.32 (d, 2H, J= 6 Hz); bromo- pyridin-2- 2- 6.5 (d, 1H, J = 8.2 Hz); pyridin-2-yl-ylamine hydroxy- 6.65 (d, 1H, J = 7.4 Hz); amino)- benzaldehyde6.77-6.81 (m, 1H); methyl]-4- 6.85-6.95 (m, 2H); 7.3 (t, 1H, J = 8.2Hz); fluoro- 7.32-7.35 (m, 1H); phenol 9.59 (s, 1H) 4 6-(2- 6-amino- 2-153 (DMSO) 4.36 (d, 2H, J = 4.8 Hz); hydroxy- pyridine-2- hydroxy- 6.73(t, 1H, J = 7.4 Hz); benzyl- carbonitrile benzaldehyde 6.81-6.84 (m,2H); amino)- 7.04-7.08 (m, 2H); 7.14 (d, 1H, J = 7.4 Hz); pyridine-2-7.46-7.54 (m, 2H); carbonitrile 9.60 (s, 1H) 5 2-[1-(6- 6-methoxy- 1-(2-109 (DMSO) 1.35 (d, 3H, J = 6.8 Hz); methoxy- pyridin-2- hydroxy- 3.66(s, 3H); pyridin-2-yl- ylamine phenyl)- 5.13-5.16 (m, 1H); 5.79 (d, 1H,J = 7.7 Hz); amino)- ethanone 5.94 (d, 1H, J = 7.8 Hz); ethyl]- 6.7 (t,1H, J = 7.3 Hz); 6.77 (t, phenol 2H, J = 8.2 Hz); 6.97 (t, 1H, J = 7.6Hz); 7.20-7.24 (m, 2H); 9.42 (s, 1H) 6 2-[(6- 2-amino-6- 2- 125 (DMSO)4.38 (d, 2H, J = 5.4 Hz); trifluoro- (trifluoro- hydroxy- 6.71-6.82 (m,3H); methyl- methyl)- benzaldehyde 6.88 (d, 1H, J = 7.2 Hz);pyridin-2-yl- pyridine 7.06 (t, 1H, J = 7.6 Hz); 7.19 (d, amino)- 1H, J= 7.4 Hz); 7.37-7.40 (m, methyl]- 1H); 7.56 (t, 1H, J = 7.8 Hz); phenol9.56 (s, 1H) 7 2-[(6- 2-amino-6- 2- not (DMSO) 4.34 (d, 1H, J = 5.8 Hz);chloro- chloro- hydroxy- determined 6.45-6.50 (m, 2H); pyridin-2-yl-pyridine benzaldehyde 6.72-6.76 (m, 2H) 6.81 (d, amino)- 1H, J = 8 Hz);7.06 (t, 1H, J = 7.6 Hz); methyl]- 7.15 (d, 1H, J = 7.4 Hz); phenol7.26-7.29 (m, 1H); 7.38 (t, 1H, J = 7.5 Hz); 9.57 (s, 1H) 8 2-[(6-ethyl-6-ethyl- 2- not (DMSO) 1.2 (t, 3H, J = 7.6 Hz); pyridin-2-yl- pyridin-2-hydroxy- determined 2.54-2.60 (q, 2H, J = 7.5 Hz); amino)- ylaminebenzaldehyde 4.31 (d, 2H, J = 6.12 Hz); methyl]- 6.33-6.38 (m, 2H);phenol 6.72-6.78 (m, 2H); 7.06-7.12 (m, 2H); 7.18 (d, 1H, J = 7.4 Hz);7.3 (t, 1H, J = 7.5 Hz); 10.88 (s, 1H) 9 2-[(6- 2-amino-6- 2-  87(CD₃OD) 1.35 (t, 3H, J = 7.0 Hz); ethoxy- ethoxy- hydroxy- 3.31-3.33 (q,2H, J = 7.0 Hz); pyridin-2-yl- pyridine benzaldehyde 4.42 (s, 2H);amino)- 5.91-5.93 (m, 1H); 6.05 (d, 1H, J = 7.8 Hz); methyl]- 6.75-6.80(m, 2H); phenol 7.05-7.10 (m, 1H); 7.19-7.22 (m, 1H); 7.29-7.33 (m, 1H)10 2-[(6- 2-amino-6- 2- not (CD₃OD) 1.26 (t, 6H, J = 6.1 Hz);isopropoxy- isopropoxy- hydroxy- determined 4.43 (s, 2H); pyridin-2-yl-pyridine benzaldehyde 5.03-5.09 (m, 1H); 5.88-5.90 (m, amino)- 1H);6.02-6.04 (m, 1H); methyl]- 6.74-6.79 (m, 2H); 7.04-7.08 (m, phenol 1H);7.19-7.21 (m, 1H); 7.3 (t, 1H, J = 7.9 Hz) 11 5-chloro-2- 6-methoxy-4-chloro- not (DMSO) 3.72 (s, 3H); 4.39 (d, [(6- pyridin-2- 2-determined 2H, J = 5.9 Hz); 5.86 (d, 1H, methoxy- ylamine hydroxy- J =7.8 Hz); 6.03 (d, 1H, J = 7.9 Hz); pyridin-2-yl- benzaldehyde 6.7 (m,1H); 6.8 (s, amino)- 1H); 6.93 (m, 1H); 7.21 (d, methyl]- 1H, J = 8.4Hz); 7.28 (t, 1H, J = 7.8 Hz); phenol 9.73 (s, 1H) 12 2-[(2-2-trifluoro- 2- 201 (DMSO) 4.34-4.47 (m, 2H); trifluoro- methyl-hydroxy- 6.55-6.85 (m, 3H); 7.1 (t, 1H, methyl- pyrimidin- benzaldehydeJ = 7.4 Hz); 7.19 (d, 1H, J = 7.3 Hz); pyrimidin-4- 4-ylamine 8.15 (d,1H, J = 5.9 Hz); ylamino)- 8.39-8.47 (m, 1H); methyl]- 9.63 (s, 1H)phenol

Example 13 2-[(6-Bromopyrazin-2-ylamino)methyl]phenol

Synthesis According to Scheme 1, Method 1b

Introduced into a 50 ml round-bottomed flask is 1 g (4.2 mmol) of2,6-dibromopyrazine (starting material 3), to which 15 ml of dimethylsulphoxide, 638 mg (4.2 mmol, 1eq) of1,8-diazabicyclo[5.4.0]undec-7-ene, and 1.03 g (8.4 mmol, 2 eq) of2-hydroxybenzylamine (starting material 4) are added; the mixture isleft stirring for 2 h at room temperature. The reaction medium isdiluted with 50 ml of ethyl acetate and then the mixture is washed with50 ml of a saturated solution of ammonium chloride, and then twice with50 ml of water. The organic phases are dried over magnesium sulphate,filtered and concentrated to dryness. The residue is purified bychromatography over silica with, as eluent, a heptane/ethyl acetate(8/2) mixture. 2-[(6-Bromopyrazin-2-ylamino)methyl]phenol is obtained inthe form of a white solid.

Melting point=168° C.

¹H NMR (DMSO): 4.36 (d, 1H, J=5.3 Hz); 6.74-6.76 (m, 1H); 6.83 (dd, 1H);7.07-7.11 (m, 1H); 7.17 (dd, 1H); 7.75 (s, 1H); 7.80-7.83 (m, 1H); 7.96(s, 1H); 9.61 (s, 1H)

Examples 14 to 18

Examples 14 to 18 are described in Table 2 below. The compounds aresynthesized according to the procedure described above, replacing thestarting materials 3 and 4 mentioned in Example 13 with the productsmentioned in Table 2.

TABLE 2 ¹H NMR - 400 MHz (s = singlet, d = doublet, t = triplet, m =multiplet, q = IUPAC Starting Starting Melting quartet, J = couplingExample # name material 3 material 4 point (° C.) constant in Hz) 142-[(2- 2,4- 2- not (CD₃OD) 4.53 (m, 2H); chloro- dichloro- hydroxy-determined 6.45 (d, 1H, J = 6.0 Hz); pyrimidin- pyrimidine benzyl-6.78-6.83 (m, 2H); 7.10-7.14 (m, 4-ylamino)- amine 1H); 7.22 (d, 1H, J =6.9 Hz); methyl]- 7.83 (m, 1H) phenol 15 2-[(2- 2,4- 2- not (CD₃OD)4.42-4.52 (m, 2H) bromo- dibromo- hydroxy- determined 6.48 (d, 1H, J =6.0 Hz); pyrimidin- pyrimidine benzyl- 6.78-6.83 (m, 2H); 7.12 (t,4-ylamino)- amine 1H, J = 8.2 Hz); methyl]- 7.21-7.23 (m, 1H); 7.76-7.86(m, 1H) phenol 16 2-[(2- 2,4- 2- not (DMSO) 2.17 (s, 3H); chloro-6-dichloro-6- hydroxy- determined 4.40 (s, 2H); 6.35 (s, 1H); 6.74 (t,methyl- methyl- benzyl- 1H, J = 7.4 Hz); 6.82 (d, 1H, pyrimidin-pyrimidine amine J = 7.9 Hz); 7.06-7.12 (m, 4-ylamino)- 2H); 8.04 (s,1H); 9.60 (s, methyl]- 1H). phenol 17 2-[(6- 2,6- 2- not (DMSO) 4.39 (d,2H, J = 5.4 Hz); chloro-4- dichloro-4- hydroxy- determined 6.73-6.84 (m,4H); trifluoro- trifluoro- benzyl- 7.080 (t, 1H, J = 7.6 Hz); methyl-methyl- amine 7.17 (d, 1H, J = 7.4 Hz); pyridin-2- pyridine 7.83 (s,1H); 9.61 (s, 1H) ylamino)- methyl]- phenol 18 2-[(6- 2,6- 2- 138 (DMSO)2.12 (s, 3H); chloro-4- dichloro-4- hydroxy- 4.32 (d, 2H, J = 5.5 Hz);6.28 (s, methyl- methyl- benzyl- 1H); 6.37 (s, 1H); 6.73 (t, pyridin-2-pyridine amine 1H, J = 7.4 Hz); 6.8 (d, 1H, J = 8 Hz); ylamino)- 7.04(t, 1H, 7.7 Hz); methyl]- 7.12-7.17 (m, 2H); 9.58 (s, phenol 1H)

Example 19 2-[(6-Methoxypyrazin-2-ylamino)methyl]phenol

Synthesis According to Scheme 2, Method 2b

Introduced into a microwave tube are 363 mg (1.29 mmol) of2-[(6-bromopyrazin-2-ylamino)methyl]phenol, prepared as describedpreviously in Example 12, to which 3 ml of methanol and 103 mg (2.58mmol, 2 eq) of sodium hydroxide are added. The reaction mixture is thenheated for 30 mins in a microwave oven at 150° C. and is then dilutedwith 50 ml of ethyl acetate. The mixture is neutralized with an ammoniumchloride solution to pH=7, decanted and the organic phase is washedtwice with 50 ml of water. The organic phase is dried over magnesiumsulphate, filtered, and concentrated to dryness. The residue is purifiedby chromatography over silica with, as eluent, heptane/ethyl acetate(7/3). 2-[(6-Methoxypyrazin-2-ylamino)methyl]phenol is obtained in theform of a white solid.

Melting point=158° C.

¹H NMR (DMSO): 3.78 (s, 1H); 4.40 (d, 2H, J=5.2 Hz); 6.73 (t, 1H, J=7.4Hz); 6.81 (d, 1H, J=8 Hz); 7.05 (t, 1H, J=7.8 Hz); 7.19 (d, 1H, J=7.4Hz); 7.26 (s, 1H); 7.31-7.32 (m, 1H); 7.50 (s, 1H); 9.55 (s, 1H).

Example 20 2-[(2-Methoxypyrimidin-4-ylamino)methyl]phenol

This compound is prepared according to the procedure described forExample 19, starting from 2-[(2-chloropyrimidin-4-ylamino)methyl]phenol.2-[(2-Methoxypyrimidin-4-ylamino)methyl]phenol is obtained in the formof a white solid.

Melting point=161° C.

¹H NMR (CD₃OD): 3.90 (s, 3H); 4.53 (s, 3H); 6.15 (d, 2H, J=6.0 Hz);6.77-6.81 (m, 2H); 7.07-7.12 (m, 1H); 7.21 (d, 1H, J=7.4 Hz); 7.78 (s,1H)

Example 21 2-[(2-Methoxy-6-methylpyrimidin-4-ylamino)methyl]phenol

This compound is prepared according to the procedure described forExample 19 above, starting from2-[(2-chloro-6-methylpyrimidin-4-ylamino)methyl]phenol.

¹H NMR (DMSO): 2.12 (s, 3H); 3.74 (s, 3H); 4.38 (m, 2H); 6.04 (s, 1H);6.73 (t, 1H, J=7.4 Hz); 6.80 (d, 1H, J=8.0 Hz); 7.06 (t, 1H, J=7.7 Hz);7.11 (d, 1H, J=7.3 Hz); 7.65 (s, 1H); 9.71 (s, 1H).

Example 22 2-[(6-Methylsulphanylpyridin-2-ylamino)methyl]phenol

Synthesis According to Scheme 2, Method 2a

Introduced into a microwave tube are 300 mg (1.28 mmol) of2-[(6-chloropyridin-2-ylamino)methyl]phenol, to which 5 ml of dimethylsulphoxide and 448 mg (6.4 mmol, 5 eq) of sodium methanethiolate areadded. The reaction mixture is heated for 16 h at 90° C. The reactionmedium is diluted with 50 ml of ethyl acetate and then washed with 50 mlof a saturated ammonium chloride solution then 2×50 ml of distilledwater. The organic phase is dried over magnesium sulphate then filteredand concentrated to dryness. The residue is purified by chromatographyover 40 g of silica with, as eluent, heptane/ethyl acetate (7/3). Theproduct obtained is put back into solution in ethyl acetate, heptane isadded until the solution becomes cloudy, it is then cooled to 0° C. andfiltered. 2-[(6-Methylsulphanylpyridin-2-ylamino)methyl]phenol isobtained in the form of a white solid.

Melting point=61° C.

¹H NMR (DMSO): 2.38 (s, 3H); 4.38 (d, 2H, J=5.6 Hz); 6.21 (d, 1H, J=8.2Hz); 6.34 (d, 1H,

J=7.4 Hz); 6.72 (t, 1H, 7.3 Hz); 6.93-6.96 (m, 1H); 7.04 (t, 1H, J=7.7Hz); 7.15 (d, 1H, J=7.1 Hz); 7.23 (t, 1H, J=7.6 Hz); 9.65 (s, 1H).

Example 23 2-[(6-Methanesulphinylpyridin-2-ylamino)methyl]phenol

160 mg (0.66 mmol) of2-[(6-methanesulphanylpyridin-2-ylamino)methyl]phenol and 406 mg (0.66mmol, 1 eq) of oxone are mixed in 20 ml of dioxane. After stirring forone hour at room temperature, the reaction medium is heated at 90° C.for 4 h. After returning to room temperature, the reaction medium isdiluted with 50 ml of ethyl acetate and then washed twice with 50 ml ofwater. The organic phase is dried over magnesium sulphate, filtered andconcentrated to dryness. The residue is purified by chromatography oversilica, eluting with a heptane/ethyl acetate (1/1) mixture.2-[(6-Methanesulphinylpyridin-2-ylamino)methyl]phenol is obtained in theform of a white solid.

Melting point=133° C.

¹H NMR (CDCl₃): 2.89 (s, 3H); 4.51 (d, 2H, J=6.2 Hz); 5.32-5.33 (m, 1H);6.5 (dd, 1H); 6.87-6.95 (m, 2H); 7.19-7.28 (m, 2H); 7.30-7.59 (m, 1H);7.62 (t, 1H, J=7.3 Hz); 9.28 (s, 1H).

Example 24 2-[(6-Methanesulphonylpyridin-2-ylamino)methyl]phenol

80 mg (0.33 mmol) of2-[(6-methanesulphanylpyridin-2-ylamino)methyl]phenol and 406 mg (0.66mmol, 2 eq) of oxone are mixed in 20 ml of dioxane and heated for 16 hat 90° C. The reaction medium is diluted with 50 ml of ethyl acetate andthen washed twice with 50 ml of water. The organic phase is dried overmagnesium sulphate, filtered and concentrated to dryness. The residue ispurified by chromatography over silica, eluting with a heptane/AcOEt(1/1) mixture. 2-[(6-Methanesulphonylpyridin-2-ylamino)methyl]phenol isobtained in the form of a slightly green solid.

¹H NMR (CDCl₃): 3.12 (s, 3H); 5.32-5.33 (m, 1H); 6.58 (d, 1H, J=7.9 Hz);6.79-6.83 (m, 1H); 6.87 (d, 1H, J=7.4 Hz); 7.3 (d, 1H, J=6.6 Hz); 7.5(t, 1H, J=7.2 Hz); 8.56 (s, 1H).

Example 25 2-[(6-Methoxypyridin-2-ylamino)methyl]-6-methylphenol

Synthesis According to Scheme 1, Method 1c

80 mg (2.1 mmol, 6 eq) of lithium aluminium hydride are added in smallfractions to a mixture of 90 mg (0.35 mmol) of2-hydroxy-N-(6-methoxypyridin-2-yl)-3-methylbenzamide in 10 ml ofdioxane. The reaction medium is heated at 80° C. for 16 h. 80 mg (2.1mmol, 6 eq) of lithium aluminium hydride are added again and the mediumis heated at 80° C. for 4 h. The reaction medium is diluted with 50 mlof ethyl acetate and washed with 50 ml of a saturated solution ofammonium chloride, and then twice with 50 ml of water. The organic phaseis dried over magnesium sulphate, filtered and concentrated to dryness.The residue is purified by chromatography over silica, eluting with aheptane/ethyl acetate (1/1) mixture.

2-[(6-methoxypyridin-2-ylamino)methyl]-6-methylphenol is obtained in theform of a white solid.

¹H NMR (CDCl₃): 2.19 (s, 3H); 3.89 (s, 3H); 4.46 (d, 2H, J=6.7 Hz); 4.75(s, 1H); 5.93-5.97 (m, 2H); 6.68 (t, 1H, J=7.4 Hz); 6.92 (d, 1H, J=7.5Hz); 7.0 (d, 1H, J=7.4 Hz); 7.27 (t, 1H, J=7.9 Hz), 9.66 (s, 1H).

Preparation of the 2-hydroxy-N-(6-methoxypyridin-2-yl)-3-methylbenzamideintermediate

10 ml of thionyl chloride are added to 1.47 g (16.11 mmol) of2-hydroxy-3-methylbenzoic acid and the reaction mixture is heated at 90°C. for 2 h. The reaction medium is concentrated to dryness byazeotroping with toluene. The residue is then put into solution in 10 mlof pyridine, to which 600 mg (4.83 mmol, 1 eq) of 2methoxypyridin-6-amine are added dropwise, and the reaction medium isleft stirring at room temperature for 1 h 30 mins. 30 ml of 1M sodiumhydroxide (19.34 mmol, 4 eq) are added and the reaction medium is heatedat 60° C. for 16 h. The reaction medium is diluted with 100 ml of ethylacetate, the aqueous phase is extracted and washed with 50 ml of ethylacetate. The aqueous phase is then acidified at 0° C. with 37% HCldropwise to pH=4. The organic phases are extracted twice with 50 ml ofethyl acetate and then they are washed twice with 50 ml of water. Theorganic phases are concentrated to dryness and the residue is purifiedby chromatography over silica, eluting with a heptane/ethyl acetate(1/1) mixture.

2-Hydroxy-N-(6-methoxypyridin-2-yl)-3-methylbenzamide is obtained in theform of a white solid.

¹H NMR (CDCl₃): 2.23 (s, 3H); 3.84 (s, 3H); 6.48 (d, 1H, J=8 Hz); 6.78(t, 1H, J=7.7 Hz); 7.26 (d, 1H, J=7.3 Hz); 7.38 (d, 1H, J=8 Hz); 7.58(t, 1H, J=8 Hz); 7.76 (d, 1H, J=7.7 Hz); 8.31 (s, 1H); 12.12 (s, 1H).

All the NMR (nuclear magnetic resonance) spectra are in agreement withthe proposed structures. The chemical shifts are expressed in parts permillion. The internal reference is tetramethylsilane. The followingabbreviations are used: CDCl₃=deuterated chloroform, DMSO=deuterateddimethyl sulphoxide, CD₃OD=deuterated methanol.

Example 26 Biological Tests

The compounds according to the invention show inhibitory properties onreceptors of AR type. This AR receptor-inhibiting activity is measuredin a transactivation test through the KdR (resting), KdA (active) andKdapp (apparent) dissociation constants according to the method set outin J. Molecular Biology (1965), 12(1), 88-118, Monod J. et al.

The expression “AR-type receptor inhibitor” means, according to theinvention, any compound which has a Kdapp dissociation constant of lessthan or equal to 1 μM, and a KdR/KdA ratio 10, in a transactivationtest.

The preferred compounds of the present invention have a dissociationconstant of less than or equal to 500 nM and advantageously less than orequal to 100 nM.

The transactivation test is carried out in the PALM (PC3 Androgenreceptor Luciferse MMTV) cell line which is a stable transfectantcontaining the PMMTV-neo-Luc (reporter gene) and pSG5puro-AR plasmids.

In this study, the affinity of each product for the 2 receptor states(KdR and KdA) is determined, as is an apparent Kd (KdApp). This constantis a result of the 2 Kd, but also depends on the initial equilibrium ofthe receptor between the active state and the resting state (L₀) and onits expression level. It is determined by means of the followingformula:1/KdApp=(L0/(1+L0))×(1/KdR)+(1/(1+L0))×(1/KdA)

To determine these constants, “cross curves” of the test product againsta reference agonist, methyltrienolone, are produced in 96-well plates.The test product is used at 10 concentrations and the reference agonistat 7 concentrations.

By way of illustration, a Kdapp of 40 nM is obtained for the compound(1), a Kdapp of 2 nM is obtained for the compound (2), a Kdapp of 8 nMis obtained for the compound (19), a Kdapp of 1000 nM is obtained forthe compound (18) and a Kdapp of 200 nM is obtained for the compound(4).

The invention claimed is:
 1. A method of preparing a compound of formula (I):

in which: R₁ represents a C₂₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy, —S(O)_(m)—C₁₋₈ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy, —(CH₂)_(n)—C₃₋₉ cycloalkyl, —(CH₂)_(n)—C₃₋₉ cycloalkyl, C₂₋₆ alkyl-OH, —(CH₂)_(n)—C₁₋₈ alkyloxy, —(CH₂)_(n)—C₁₋₆ fluoroalkyl, —(CH₂)_(p)—O—C₁₋₆ fluoroalkyl, COR_(a), CN, NO₂ or NR₈R₉ group, a halogen or a phenyl or heteroaryl group comprising either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulphur atom and 1 or 2 nitrogen atom(s); wherein the phenyl and heteroaryl groups can optionally be substituted with one to three identical or different R_(b) groups, R₂ and R₃ are identical or different and represent a hydrogen atom or a C₁₋₉ alkyl, C₃₋₉ cycloalkyl, C₁₋₆ fluoroalkyl, —(CH₂)_(r)—C₃₋₉ cycloalkyl, —C₂₋₆ alkyl-OH, —(CH₂)_(r)—C₁₋₆ alkyloxy, —(CH₂)_(r)—C₃₋₇ cycloalkyl, —(CH₂)_(r)—C₁₋₆ fluoroalkyl, or —(CH₂)_(q)—O—C₁₋₆ fluoroalkyl group, optionally, the R₂ and R₃ groups can form, with the carbon atom which bears them, a C₃₋₉ cycloalkyl group or a heterocycle, R₄, R₅, R₆, R₇ are identical or different and represent either a hydrogen atom or a C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy, —S(O)_(s)—C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy, —(CH₂)_(t)—C₃₋₉ cycloalkyl, —(CH₂)_(t)—C₃₋₉ cycloalkyl, —C₁₋₆ alkyl-OH, —(CH₂)_(t)—C₁₋₆ alkyloxy, —(CH₂)_(t)—C₁₋₆ fluoroalkyl, —(CH₂)_(u)—O—C₁₋₆ fluoroalkyl, COR_(d), CN or NR_(8′)R_(9′) group, or a halogen or a phenyl or heteroaryl group comprising either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulphur atom and 1 or 2 nitrogen atom(s); these phenyl and heteroaryl groups can optionally be substituted with one to three identical or different R_(c) groups, X represents CH or N; Y represents either a nitrogen atom, or a carbon atom substituted with a C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy, —S(O)_(v)—C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy, —(CH₂)_(l)—C₃₋₉ cycloalkyl, —(CH₂)_(l)—C₃₋₉ cycloalkyl, C₁₋₆ alkyl-OH, —(CH₂)_(l)—C₁₋₆ alkyloxy, —(CH₂)_(l)—C₁₋₆ fluoroalkyl, —(CH₂)_(w)—O—C₁₋₆ fluoroalkyl, COR₈, CN, NR₁₀R₁₁ or NO₂ group, a hydrogen atom or a halogen or a phenyl or heteroaryl group comprising either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulphur atom and 1 or 2 nitrogen atom(s); these phenyl and heteroaryl groups can optionally be substituted with one to three identical or different R_(b) groups, R_(a), R_(d) and R_(e) are identical or different and represent a C₁₋₆ alkyl, C₁₋₆ alkyloxy or NR₁₂R₁₃ group; R_(b) and R_(c) are identical or different and represent a halogen, or a C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy, —S(O)_(i)—C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy, —(CH₂)_(i)—C₃₋₇ cycloalkyl, OH, —(CH₂)_(i)—C₃₋₇ cycloalkyl, C₁₋₆ alkyl-OH, —(CH₂)_(i)—C₁₋₆ alkyloxy, fluoroalkyl, —(CH₂)_(z)—O—C₁₋₆ fluoroalkyl, COR_(a), CN or NR₁₄R₁₅ group; R₈ and R_(8′) are identical or different and represent a C₁₋₆ alkyl, C₃₋₇ cycloalkyl, —(CH₂)_(f)—C₃₋₇ cycloalkyl or —(CH₂)_(f)—C₁₋₆ fluoroalkyl group; R₉, R_(9′), R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₅ are identical or different and represent a hydrogen atom or a C₁₋₆ alkyl, C₃₋₇ cycloalkyl, —(CH₂)_(g)—C₃₋₇ cycloalkyl or —(CH₂)_(g)—C₁₋₆ fluoroalkyl group; optionally, the R₈ and R₉ groups can form, with the nitrogen atom which bears them, a heterocycle; optionally, the R_(8′) and R_(9′) groups can form, with the nitrogen atom which bears them, a heterocycle; optionally, the R₁₀ and R₁₁ groups can form, with the nitrogen atom which bears them, a heterocycle; optionally, the R₁₂ and R₁₃ groups can form, with the nitrogen atom which bears them, a heterocycle; optionally, the R₁₄ and R₁₅ groups can form, with the nitrogen atom which bears them, a heterocycle; f, g, i, l, n, r and t are different or identical and are equal to 1, 2 or 3; j, m, s and v are different or identical and are equal to 0, 1 or 2; p, q, u, w and z are different or identical and are equal to 2, 3 or 4; and also a pharmaceutically acceptable salt, solvate, hydrate, conformer or rotamer thereof, the method comprising: (a) reacting an aldehyde (II) or a benzyl ketone (II) with an amine (III) in the presence of a reducing agent;

(b) reacting a benzyl amine (VI) with a heterocycle (V) in the presence of a base; or

(c) reacting an amide intermediate (VII) with a reactive hydrogen donor


2. The method according to claim 1, wherein the amide intermediate (VII) is prepared by reacting an acyl chloride (VI) with an amine (III)


3. The method according to claim 1, wherein the reducing agent is sodium triacetoxyborohydride.
 4. The method according to claim 1, wherein the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.
 5. The method according to claim 1, wherein the reactive hydrogen donor is lithium aluminum anhydride.
 6. The method according to claim 1, wherein X represents a carbon atom and Y represents a carbon atom optionally substituted with one of the groups as defined in claim
 1. 7. The method according to claim 6, wherein Y represents a carbon substituted with a member selected from the group consisting of a methyl, ethyl, isopropyl, cyclopropyl, CF₃, CONH₂, CO₂CH₃, CO₂CH₂CH₃, CN, NO₂, SCH₃ or SCH₂CH₃ group, a hydrogen atom, a halogen, a OCF₃, OCH₃, OCH₂CH₃ or OCH(CH₃)₂ group.
 8. The method according to claim 1, wherein R1 represents a halogen, an ethyl, an isopropyl, a trifluoromethyl, a nitrile, a nitro, a methoxy, an ethoxy, an isopropoxy, a thiomethyl, a thioethyl or a thioisopropyl group.
 9. The method according to claim 8, wherein R1 represents a halogen, a methoxy, an ethoxy, a thiomethyl, a thioethyl or a trifluoromethyl group.
 10. The method according to claim 1, wherein the R2 and R3 groups can form tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, tetrahydro-1-oxythiopyran or tetrahydro-1,1-dioxythiopyran.
 11. The method according to claim 1, wherein the R8 and R9 groups can form azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
 12. The method according to claim 1, wherein the R10 and R11 groups can form azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
 13. The method according to claim 1, wherein the R12 and R13 groups can form azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
 14. The method according to claim 1, wherein the R14 and R15 groups can form azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
 15. The method according to claim 1, wherein the compound is selected from the group consisting of: 2-[(6-Methoxypyridin-2-ylamino)methyl]phenol; 2-[(6-Bromopyridin-2-ylamino)methyl]phenol; 2[(6-Bromopyridin-2-ylamino)methyl]-4-fluorophenol; 6-(2-Hydroxybenzylamino)pyridine-2-carbonitrile; 2-[1-(6-Methoxypyridin-2-ylamino)ethyl]phenol; 2-[(6-Trifluoromethylpyridin-2-ylamino)methyl]phenol; 2-[(6-Chloropyridin-2-ylamino)methyl]phenol; 2-[(6-Ethylpyridin-2-ylamino)methyl]phenol; 2-[(6-Ethoxypyridin-2-ylamino)methyl]phenol; 2[(6-Isopropoxypyridin-2-ylamino)methyl]phenol; 5-Chloro-2-[(6-methoxypyridin-2-ylamino)methyl]phenol; 2[(2-Trifluoromethylpyrimidin-4-ylamino)methyl]phenol; 2-[(6-Bromopyrazin-2-ylamino)methyl]phenol; 2-[(2-Chloropyrimidin-4-ylamino)methyl]phenol; 2-[(2-Bromopyrimidin-4-ylamino)methyl]phenol; 2-[(2-Chloro-6-methylpyrimidin-4-ylamino)methyl]phenol; 2-[(6-Chloro-4-trifluoromethylpyridin-2-ylamino)methyl]phenol; 2-[(6-Chloro-4-methylpyridin-2-ylamino)methyl]phenol; 2-[(6-Methoxypyrazin-2-ylamino)methyl]phenol; 2-[(2-Methoxypyrimidin-4-ylamino)methyl]phenol; 2-[(2-Methoxy-6-methylpyrimidin-4-ylamino)methyl]phenol; 2-[(6-Methylsulphanylpyridin-2-ylamino)methyl]phenol; 2-[(6-Methanesulphinylpyridin-2-ylamino)methyl]phenol; 2-[(6-Methanesulphonylpyridin-2-ylamino)methyl]phenol; 2-[(6-Methoxypyridin-2-ylamino)methyl]-6-methylphenol; 2-[(4-Bromo-6-methoxypyridin-2-ylamino)methyl]phenol; 2[(6-Bromo-2-methoxypyrimidin-4-ylamino)methyl]phenol; 2-[(4-Chloro-6-methoxypyridin-2-ylamino)methyl]phenol; 2[(6-Bromo-2-methoxypyrimidin-4-ylamino)methyl]phenol; 2-[(4-Bromo-6-methoxypyridin-2-ylamino)methyl]-6-fluorophenol; 2[(4-Bromo-6-methoxypyridin-2-ylamino)methyl]-5-fluorophenol; 2-[(4-Bromo-6-methoxypyridin-2-ylamino)methyl]-3-fluorophenol; 2[(4-Bromo-6-methoxypyridin-2-ylamino)methyl]-4-fluorophenol; 2-[(6-Bromo-2-methoxypyrimidin-4-ylamino)methyl]-4-fluorophenol; 2-[(4-Chloro-6-methoxypyridin-2-ylamino)methyl]-4-fluorophenol; 2-[(6-Chloro-2-methoxypyrimidin-4-ylamino)methyl]-4-fluorophenol; 2-[1-(4-Bromo-6-methoxypyridin-2-ylamino)ethyl]phenol; 2-[1-(4-Bromo-6-methoxypyridin-2-ylamino)propyl]phenol; 2-[1-(6-Bromo-4-methylpyridin-2-ylamino)-1-methylethyl]phenol; 2-[1-(4-Bromo-6-methoxypyridin-2-ylamino)propyl]-4-fluorophenol; 2-[1-(6-Bromopyridin-2-ylamino)propyl]-4-fluorophenol; 4-Fluoro-2-[(6-methoxypyridin-2-ylamino)methyl]phenol; 4-Fluoro-2-[1-(6-methoxypyridin-2-ylamino)ethyl]phenol; 4-Fluoro-2-[1-(6-methoxypyridin-2-ylamino)propyl]phenol; 2-[(6-Bromo-4-methoxypyridin-2-ylamino)methyl]phenol; 2-[(6-Bromo-4-methylpyridin-2-ylamino)methyl]phenol; and -[(6-Chloro-4-methoxypyridin-2-ylamino)methyl]phenol and a pharmaceutically acceptable salt, solvate, hydrate or rotamer thereof. 